University of Oulu

Nilsson, K. H., Wu, J., Gustafsson, K. L., El Shahawy, M., Koskela, A., Tuukkanen, J., Tuckermann, J., Henning, P., Lerner, U. H., Ohlsson, C., & Movérare-Skrtic, S. (2022). Estradiol and RSPO3 regulate vertebral trabecular bone mass independent of each other. American Journal of Physiology-Endocrinology and Metabolism, 322(3), E211–E218.

Estradiol and RSPO3 regulate vertebral trabecular bone mass independent of each other

Saved in:
Author: Nilsson, Karin H.1; Wu, Jianyao1; Gustafsson, Karin L.1;
Organizations: 1Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
2Department of Anatomy and Cell Biology, Faculty of Medicine, Institute of Cancer Research and Translational Medicine, University of Oulu, Oulu, Finland
3Institute of Comparative Molecular Endocrinology (CME), University of Ulm, Ulm, Germany
4Region V€astra G€otaland, Department of Drug Treatment, Sahlgrenska University Hospital, Gothenburg, Sweden
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.8 MB)
Persistent link:
Language: English
Published: American Physiological Society, 2022
Publish Date: 2022-09-30


Osteoporosis is an age-dependent serious skeletal disease that leads to great suffering for the patient and high social costs, especially as the global population reaches higher age. Decreasing estrogen levels after menopause result in a substantial bone loss and increased fracture risk, whereas estrogen treatment improves bone mass in women. RSPO3, a secreted protein that modulates WNT signaling, increases trabecular bone mass and strength in the vertebrae of mice, and is associated with trabecular density and risk of distal forearm fractures in humans. The aim of the present study was to determine if RSPO3 is involved in the bone-sparing effect of estrogens. We first observed that estradiol (E2) treatment increases RSPO3 expression in bone of ovariectomized (OVX) mice, supporting a possible role of RSPO3 in the bone-sparing effect of estrogens. As RSPO3 is mainly expressed by osteoblasts in the bone, we used a mouse model devoid of osteoblast-derived RSPO3 (Runx2-creRspo3flox/flox mice) to determine if RSPO3 is required for the bone-sparing effect of E2 in OVX mice. We confirmed that osteoblast-specific RSPO3 inactivation results in a substantial reduction in trabecular bone mass and strength in the vertebrae. However, E2 increased vertebral trabecular bone mass and strength similarly in mice devoid of osteoblast-derived RSPO3 and control mice. Unexpectedly, osteoblast-derived RSPO3 was needed for the full estrogenic response on cortical bone thickness. In conclusion, although osteoblast-derived RSPO3 is a crucial regulator of vertebral trabecular bone, it is required for a full estrogenic effect on cortical, but not trabecular, bone in OVX mice. Thus, estradiol and RSPO3 regulate vertebral trabecular bone mass independent of each other.

see all

Series: American journal of physiology. Endocrinology and metabolism
ISSN: 0193-1849
ISSN-E: 1522-1555
ISSN-L: 0193-1849
Volume: 322
Issue: 3
Pages: E211 - E218
DOI: 10.1152/ajpendo.00383.2021
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: This study was supported by the Swedish Research Council,the Swedish Foundation for Strategic Research, the Swedish state under the agreement between the Swedish Government and the county councils, the ALF-agreement in Gothenburg (Grants238261, 226481, and 237551), the Inga Britt and Arne Lundberg Foundation, the Royal 80 Year Fund of King Gustav V, the Torsten and Ragnar Söderberg’s Foundation, the Knut and Alice Wallenberg Foundation, the Novo Nordisk Foundation, and the Adlerbertska Research Foundation.
Copyright information: © 2022 The Authors. Licensed under Creative Commons Attribution CC-BY 4.0. Published by the American Physiological Society.